Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice

被引：224

作者：

Cokorinos, Emily C. ^{[1
]}

Delmore, Jake ^{[1
]}

Reyes, Allan R. ^{[1
]}

Albuquerque, Bina ^{[1
]}

Kjobsted, Rasmus ^{[2
]}

Jorgensen, Nicolas O. ^{[2
]}

Tran, Jean-Luc ^{[1
]}

Jatkar, Aditi ^{[1
]}

Cialdea, Katherine ^{[1
]}

Esquejo, Ryan M. ^{[1
]}

Meissen, John ^{[3
]}

Calabrese, Matthew F. ^{[4
]}

Cordes, Jason ^{[5
]}

Moccia, Robert ^{[6
]}

Tess, David ^{[3
]}

Salatto, Christopher T. ^{[1
]}

Coskran, Timothy M. ^{[5
]}

Opsahl, Alan C. ^{[5
]}

Flynn, Declan ^{[5
]}

Blatnik, Matthew

Li, Wenlin

Kindt, Erick ^{[3
]}

Foretz, Marc ^{[7
,8
,9
]}

Viollet, Benoit ^{[7
,8
,9
]}

Ward, Jessica ^{[1
]}

Kurumbail, Ravi G.

Kalgutkar, Amit S. ^{[3
]}

Wojtaszewski, Jorgen F. P. ^{[2
]}

Cameron, Kimberly O. ^{[10
]}

Miller, Russell A. ^{[1
]}

机构：

[1] Pfizer Inc, Cardiovasc Metab & Endocrine Dis Res Unit, Cambridge, MA 02139 USA

[2] Univ Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Sect Mol Physiol, DK-1017 Copenhagen, Denmark

[3] Pfizer Inc, Pharmacokinet Dynam & Metab, Groton, CT 06340 USA

[4] Pfizer Inc, Pfizer Worldwide Res & Dev, Worldwide Med Chem, Groton, CT 06340 USA

[5] Pfizer Inc, Drug Safety Res & Dev, Groton, CT 06340 USA

[6] Pfizer Inc, Computat Sci, Cambridge, MA 02139 USA

[7] INSERM, Inst Cochin, U1016, F-75014 Paris, France

[8] CNRS, F-75014 Paris, France

[9] Univ Paris 05, Sorbonne Paris Cite, F-75006 Paris, France

[10] Pfizer Inc, Cardiovasc Metab & Endocrine Dis Med Chem, Cambridge, MA 02139 USA

来源：

CELL METABOLISM | 2017年 / 25卷 / 05期

关键词：

PROTEIN-KINASE; HEPATIC GLUCONEOGENESIS; INSULIN SENSITIVITY; STRUCTURAL BASIS; CELL-GROWTH; METFORMIN; EXERCISE; PHOSPHORYLATION; PATHWAY; CONTRACTION;

D O I：

10.1016/j.cmet.2017.04.010

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The AMP-activated protein kinase (AMPK) is a potential therapeutic target for metabolic diseases based on its reported actions in the liver and skeletal muscle. We evaluated two distinct direct activators of AMPK: a non-selective activator of all AMPK complexes, PF-739, and an activator selective for AMPK beta 1-containing complexes, PF-249. In cells and animals, both compounds were effective at activating AMPK in hepatocytes, but only PF-739 was capable of activating AMPK in skeletal muscle. In diabetic mice, PF-739, but not PF-249, caused a rapid lowering of plasma glucose levels that was diminished in the absence of skeletal muscle, but not liver, AMPK heterotrimers and was the result of an increase in systemic glucose disposal with no impact on hepatic glucose production. Studies of PF-739 in cynomolgus monkeys confirmed translation of the glucose lowering and established activation of AMPK in skeletal muscle as a potential therapeutic approach to treat diabetic patients.

引用

页码：1147 / +

页数：23

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